Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry

In the paramyxovirus cell entry process, receptor binding triggers conformational changes in the fusion protein (F) leading to viral and cellular membrane fusion. Peptides derived from C-terminal heptad repeat (HRC) regions in F have been shown to inhibit fusion by preventing formation of the fusogenic six-helix bundle. We recently showed that the addition of a cholesterol group to HRC peptides active against Nipah virus targets these peptides to the membrane where fusion occurs, dramatically increasing their antiviral effect. In this work, we report that unlike the untagged HRC peptides, which bind to the postulated extended intermediate state bridging the viral and cell membranes, the cholesterol tagged HRC-derived peptides interact with F before the fusion peptide inserts into the target cell membrane, thus capturing an earlier stage in the F-activation process. Furthermore, we show that cholesterol tagging renders these peptides active in vivo: the cholesterol-tagged peptides cross the blood brain barrier, and effectively prevent and treat in an established animal model what would otherwise be fatal Nipah virus encephalitis. The in vivo efficacy of cholesterol-tagged peptides, and in particular their ability to penetrate the CNS, suggests that they are promising candidates for the prevention or therapy of infection by Nipah and other lethal paramyxoviruses

Rhabdoviruses as Vaccine Vectors for Veterinary Pathogens

Rhabdoviruses are simple RNA viruses, which are open to genetic manipulation. Recombinant vector vaccines based on vesicular stomatitis virus (VSV) or rabies virus (RABV) are capable of inducing strong and protective immune responses in animals and humans as exemplified by the VSV-based Ebola virus vaccine. As several rhabdoviruses are harmful for animals and/or humans, the recombinant vector vaccine derived from them needs to be properly attenuated. Single-cycle vector vaccines and interferon-stimulating viruses represent attractive strategies to achieve attenuation. VSV and RABV are notifiable Office International des Epizooties (OIE)-listed pathogens, and this has impeded their general use in the veterinary field. However, vector vaccines based on different non-notifiable rhabdoviruses may represent an attractive alternative